A model of human B cell activation, proliferation, and terminal differentiation was established. Human B cell subsets were identified and separated on the basis of their state of activation by employing cell sizing techniques, the sequential and selective expression of cell surface markers, the synthesis of RNA or DNA, and the selective response to growth and differentiation factors. The selective sensitivity of various phases of the human B cell cycle to pharmacologic modulation by agents such as cyclosporin A, corticosteroids, and cytotoxic agents was demonstrated. In an antigen-specific system of human B cell activation, immunoregulatory T cell and monocyte subsets were identified, and the diverse mechanisms of their modulation of B cell responses were delineated. Radiation sensitivity and precursor frequency studies of immunoregulatory T cells as well as the limiting dilution of analyses of antigen-specific B cells were performed. The phenomenon of high antigen concentration blockade of B cell differentiation in the face of normal B and T cell proliferation was described. The relationship between the primary activation of B cells by antigen in vivo and the subsequent antigen-dependent driving of these cells towards terminal differentiation in vitro by nonspecific, non-major histocompatibility complex-restricted soluble T cell factors was studied. For the first time in the human system, antigen-binding B cells were identified and purified from the peripheral blood following in vivo immunization with soluble antigens such as pneumococcal polysaccharide. The positive and negative influences of allogeneic effects on antigen-specific human B cell responses were studied, and the T cell subsets responsible for these effects were described. The genetic restriction of monocyte--T cell interactions in the induction of T cell-dependent B cell responses as well as the role of Ia and certain cell surface activation molecules in the antigen-induced activation of T cell-dependent B cell responses were described.